Dysregulated Network of Immune, Endocrine and Metabolic Markers is Associated to More Severe Human Chronic Chagas Cardiomyopathy

Abstract

Individuals who are infected with Trypanosoma cruzi develop chronic Chagas cardiomyopathy (CCC), which is a complication involving a series of immune pathogenetic mechanisms, although an association between immune and metabolic alterations was more recently proposed. Accordingly, we investigated the immuno-metabolic response in chagasic patients and their possible influence on CCC pathogenesis. To this end, T. cruzi-seropositive (asymptomatic or with CCC) and sero-negative individuals were studied. Serum tumour necrosis factor (TNF)-α, interleukin (IL)-6, adipocytokines and the expression of their receptors in peripheral blood mononuclear cell (PBMC) were evaluated, together with other factors influencing the immune response. CCC patients showed major metabolic and hormonal abnormalities, in parallel with increased IL-6 and leptin serum levels. TNF-α receptor s, leptin and adiponectin receptors (ObR and Adipo-Rs respectively), as well as PPAR-γ expression in PBMCs from CCC patients were compatible with a counteracting response leading to an unfavourable immune-metabolic profile. These results suggest that persistently increased levels of immune-metabolic pro-inflammatory mediators along with the adverse endocrine anti-inflammatory response of CCC individuals, may contribute to the underlying mechanisms dealing with myocardial tissue damage.

IL-10-Dependent and -Independent Mechanisms Are Involved in the Cardiac Pathology Modulation Mediated by Fenofibrate in an Experimental Model of Chagas Heart Disease

“…In this regard, several researchers have shown increased expression of pro-inflammatory cytokines in serum as well as in tissue in different experimental models of Chagas disease (52,53), as well as associations between the increase in their concentration during the acute stage of the disease and the loss of contractile capability of myofibers during the chronic phase (54). Others have shown elevated pro-inflammatory cytokines in serum and heart sections of patients with CCC in comparison with patients with chronic asymptomatic infection (55)(56)(57)(58). Interestingly, SNP polymorphisms in the genes encoding for pro-inflammatory cytokines, are involved in variations in serum concentration of the coded cytokines and might be related to the progression of CCC (59).…”

Evidence in Favor of an Alternative Glucocorticoid Synthesis Pathway During Acute Experimental Chagas Disease

“…Increasing amount of the experimental evidence indicated that the degree of dissociation between ACTH and GC secretion is of clinical relevance, as it has been associated with the level of complications of sepsis, surgery, malignant disease, and depression. In the context of human Chagas disease, beyond the disturbed HPA response in terms of the CG/dehydroepiandrosterone ratio, GC levels fell within normal levels (57,58). Nevertheless, it is possible that during the acute symptomatic phase of human Chagas disease, as seen in the highly lethal oral acute infection (28,29), the regulation of GC production may be like the one seen in the experimental model.…”

TLR4 agonist protects against Trypanosoma cruzi acute lethal infection by decreasing cardiac parasite burdens

“…55 Importantly, IL-6 has been found to be significantly elevated in the serum of CCC patients and experimental animal models of CCC. [56][57][58] IL-6 is a pleiotropic cytokine that can induce both inflammatory and fibrotic pathways through STAT3 signalling. 59 Chronic activation of STAT3 in the heart has been demonstrated to cause excessive inflammation, ventricular rupture and death.…”